Communications to the Editor
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14 2441
see: (a) DeVita, R. J .; Wyvratt, M. J . Benzolactam Growth
hormone Secretagogues. Drugs Future 1996, 21, 273-281. (b)
Nargund, R. P.; Van der Ploeg, L. H. T. Growth Hormone
Secretagogues. Ann. Rep. Med. Chem. 1997, 32, 221-230.
(6) (a) Smith, R. G.; Cheng, K.; Schoen, W. R.; Pong, S.-S.; Hickey,
G.; J acks, T.; Butler, B.; Chan, W. W.-S.; Chaung, L.-Y. P.;
J udith, F.; Taylor, J .; Wyvratt, M. J .; Fisher, M. H. A Nonpep-
tidyl Growth Hormone Secretagogue. Science 1993, 260, 1640-
1643. (b) Schoen, W. R.; Pisano, J . M.; Prendergast, K.; Wyvratt,
M. J .; Fisher, M. H.; Cheng, K.; Chan, W.-S.; Butler, B.; Smith,
R. G.; Ball, R. G. A Novel 3-Substituted Benzazepinone Growth
Hormone Secretagogue (L-692,429). J . Med. Chem. 1994, 37,
897-906.
and enzyme assays in which no significant binding was
observed at 10 µM. These included opiate, neurokinin,
adrenergic, somatostatin, cholecystokinin, bradykinin,
vasopressin, and benzodiazepine assays.
4 was active when administered iv to rats (0.025 mg/
kg) and beagles (0.005 mg/kg). When administered
orally to beagles at doses of 0.25, 0.50, and 1.0 mg/kg,
4 increased GH levels with mean peaks of 10, 38, and
99 ng/mL versus 4 ng/mL for placebo. Despite its higher
GH peaks, 4 elicited smaller GH areas under the curve
compared to 2 reflecting its short duration of action. It
was active for only 2 h at the 0.5 mg/kg oral dose,
whereas 2 at the same dose maintained elevations in
GH up to 8 h. When 4 was administered daily at 0.50
mg/kg for 7 days, the GH responses on days 1, 4, and 7
were similar. IGF-1 increases of 21-27% occurred at
8 h after dosing on each of the sampling days, but the
pretreatment levels on days 4 and 7 were not increased
over day 1 baseline levels. Modestly elevated cortisol
responses (2-fold) were similar on these days. These
results are in contrast to results with 2 at the same
dosage where both the GH and cortisol responses were
decreased on days 4 and 7 relative to the first day of
treatment.
Pharmacokinetics of 4 were studied in male Sprague-
Dawley rats and male beagle dogs. After an oral dose
of 26.3 mg/kg to rats, Cmax was 182.4 ng/mL that
occurred between 15 and 60 min. Bioavailability was
12.1%. At an iv dose of 5.5 mg/kg, Clp, Vdss, and t1/2 in
rats were 206 mL/min/kg, 2.7 L/kg, and 0.4 h. Following
oral administration of 3.8 mg/kg 4 to dogs, the average
Cmax was 560 ng/mL with a Tmax that ranged between
15 and 30 min. Bioavailability was 29%. After iv dosing
of 0.46 mg/kg, Clp, Vdss, and t1/2 of 4 were 23.0 mL/min/
kg, 1.3 L/kg, and 1.2 h.
(7) Patchett, A. A.; Nargund, R. P.; Tata, J . R.; Chen, M. H.;
Barakat, K. H.; J ohnston, D. B. R.; Cheng, K.; Chan, W. W.-S.;
Butler, B.; Hickey, G.; J acks, T.; Schleim, K.; Pong, S.-S.;
Chaung, L.-Y. P.; Chen, H. Y.; Frazier, E.; Leung, K. H.; Chiu,
S.-H. L.; Smith, R. G. Design And Biological Activities Of L-163,-
191 (MK-0677): A Potent, Orally Active Growth Hormone
Secretagogue. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 7001-7005.
(8) (a) Pong, S. S.; Chaung, L. Y.; Dean, D. C.; Nargund, R. P.;
Patchett, A. A.; Smith, R. G. Identification Of A New G-Protein-
Linked Receptor For Growth Hormone Secretagogues. Mol.
Endocrinol. 1996, 10, 57-61. (b) Howard, A. D.; Feighner, S.
D.; Cully, D. F.; Arena, J . P.; Liberator, P. A.; Rosenblum, C. I.;
Hamelin, M.; Hreniuk, D. L.; Palyha, O. C.; Anderson, J .; Paress,
P. S.; Diaz, C.; Chou, M.; Liu, K. K.; McKee, K. K.; Pong, S.-S.;
Chaung, L.-Y.; Elbrecht, A.; Dashkevicz, M.; Heavens, R.; Rigby,
M.; Sirinathsinghji, D. J . S.; Dean, D. C.; Melillo, D. G.; Patchett,
A. A.; Nargund, R.; Griffin, P. R.; DeMartino, J . A.; Gupta, S.
K.; Schaeffer, J . M.; Smith, R. G.; Van Der Ploeg, L. H. T. A
Receptor In Pituitary And Hypothalamus That Functions In
Growth Hormone Release. Science 1996, 273, 974-977.
(9) (a) Chen, M.-H.; Steiner, M. G.; Patchett, A. A.; Cheng, K.; Wei,
L.; Chan, W. W.-S.; Butler, B.; J acks, T. M.; Smith, R. G.
Analogues Of The Orally Active Growth Hormone Secretagogue
L-162,752. Bioorg. Med. Chem. Lett. 1996, 6, 2163-2168. (b)
Nargund, R. P.; Chen, M.-H.; J ohnston, D. B. R.; Barakat, K.
J .; Tata, J . R.; Cheng, K.; J acks, T. M.; Chan, W. W.-S.; Butler,
B.; Hickey, G. J .; Smith, R. G.; Patchett, A. A. Peptidomimetic
Growth Hormone Secretagogues: Synthesis And Biological
Activities Of Analogues Varied At The Indole Unit Of The
Prototypical Spiropiperidine L-162,752. Bioorg. Med. Chem. Lett.
1996, 6, 1731-1736. (c) Tata, J . R.; Nargund, R. J .; Murphy, M.
M.; J ohnston, D. B. R.; Patchett, A. A.; Cheng, K.; Wei, L.; Chan,
W. W.-S.; Butler, B.; J acks, T. M.; Hickey, G.; Smith, R. G. The
Synthesis And Activity Of Spiroindane Growth Hormone Secre-
tagogues. Bioorg. Med. Chem. Lett. 1997, 7, 663-668. (d) Yang,
L.; Morriello, G.; Prendergast, K.; Cheng, K.; J acks, T.; Chan,
W. W.-S.; Schleim, K. D.; Smith, R. G.; Patchett, A. A. Potent
3-spiropiperidine growth hormone secretagogues. Bioorg. Med.
Chem. Lett. 1998, 8, 107-112.
(10) (a) J acks, T.; Smith, R.; J udith, F.; Schleim, K.; Frazier, E.; Chen,
H.; Krupa, D.; Hora, D., J r.; Nargund, R.; Patchett, A.; Hickey,
G. MK-0677, A Potent, Novel, Orally Active Growth Hormone
(GH) Secretagogue: GH, Insulin-Like Growth Factor I, And
Other Hormonal Responses In Beagles. Endocrinology 1996, 137,
5284-5289. (b) Hickey, G. J .; J acks, T. M.; Schleim, K. D.;
Frazier, E.; Chen, H. Y.; Krupa, D.; Feeney, W.; Nargund, R.
P.; Patchett, A. A.; Smith, R. G. Repeat Administration Of The
GH Secretagogue MK-0677 Increases And Maintains Elevated
IGF-I Levels In Beagles. J . Endocrinol. 1997, 152, 183-192.
(11) Pihoker, C.; Badger, T. M.; Reynolds, G. A.; Bowers, C. Y.
Treatment Effects Of Intranasal Growth Hormone Releasing
Peptide-2 In Children With Short Stature. J . Endocrinol. 1997,
155, 79-86.
(12) Tata, J . R.; Lu, Z.; J acks, T. M.; Schleim, K. D.; Cheng, K.; Wei,
L.; Chan, W. W.-S.; Butler, B.; Tsou, N.; Leung, K.; Chiu, S.-H.
L.; Hickey, G.; Smith, R. G.; Patchett, A. A. The Design And
Synthesis Of Orally Active Short Duration Spiroindane Growth
Hormone Secretagogues. Bioorg. Med. Chem. Lett. 1997, 7,
2319-2324.
In summary, we report here a potent, short-duration
GH secretagogue that also has excellent oral bioavail-
ability. The discovery provided a very useful tool for
long-term efficacy studies of a short-acting secretagogue.
Ack n ow led gm en t. We would like to thank Amy
Bernick for mass spectrometry support, Dr. Richard Ball
and Ms. Nancy Tsou for X-ray crystallography, and Dr.
Gerard Kieczykowski of the Basic Chemistry Prepara-
tion Laboratory for large-scale synthesis of key inter-
mediates.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details for the synthesis of compound 4 (4 pages). Ordering
information is given on any current masthead page.
Refer en ces
(1) For a review on GH, see: Strobl, J . S.; Thomas, M. J . Human
Growth Hormone. Pharmacol. Rev. 1994, 46, 1-34.
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J ohanson, A. Adult Height In Growth Hormone (GH)-Deficient
Children Treated With Biosynthetic GH. J . Clin. Endocrinol.
Metab. 1997, 82, 418-420.
(3) Bouillanne, O.; Rainfray, M.; Tissandier, O.; Nasr, A.; Lahlou,
A.; Cnockaert, X.; Piette, F. Growth Hormone Therapy In Elderly
People: An Age-Delaying Drug? Fundam. Clin. Pharmacol.
1996, 10, 416-430.
(4) Momany, F. A.; Bowers, C. Y.; Reynolds, G. A.; Chang, D.; Hong,
A.; Newlander, K. Design, Synthesis, And Biologoical Activity
Of Peptides Which Release Growth Hormone In Vitro. Endo-
crinology 1981, 108, 31-39.
(5) For a recent review on GHRP, see: Ghigo, E.; Arvat, E.; Muccioli,
G.; Camanni, F. Growth Hormone-Releasing Peptides. Eur. J .
Endocrinol. 1997, 136, 445-460. For recent reviews on GHS,
(13) Cheng, K.; Chan, W. W.-S.; Barreto, A.; Convey, E. M.; Smith,
R. G. The Synergistic Effects Of His-D-Trp-Ala-Trp-D-Phe-Lys-
NH2 On Growth Hormone (GH)-Releasing Factor-Stimulated
GH Release And Intracellular Adenosine 3′,5′-Monophosphate
Accumulation In Rat Primary Pituitary Cell Culture. Endocri-
nology 1989, 124, 2791-2798.
(14) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.;
Anderson, P. S.; Chang, R. S. L.; Lotti, V. J .; Cerino, D. J .; Chen,
T. B.; Kling, P. J .; Kunkel, K. A.; Springer, J . P.; Hirshfield, J .
Methods For Drug Discovery: Development Of Potent, Selective,
Orally Effective Cholecystokinin Antagonists. J . Med. Chem.
1988, 31, 2235-2246.
(15) Detailed SAR studies will be reported in due course.
J M9800191